This project has focused on aspects of the mucosal immune system and the capacity of gp120 to impact the function of immune cells associated with the mucosal immune system. These studies were undertaken as a result of our demonstration of an interaction between the gut mucosal homing receptor, integrin alpha4beta7 and HIV gp120, which led to new questions related to gp120-mediated signal transduction. We tested this hypothesis in a non-human primate (NHP) model of HIV/SIV infection, and determined that an antibody specific for alpha4beta7 prevented transmission in a rhesus macaque model of mucosal transmission. Of note, this antibody is a primatized version of Vedolizumab, an FDA approved drug employed for the treatment of inflammatory bowel diseases (IBDs). We subsequently tested the impact of this alpha4beta7 antagonist in an in vivo NHP study in the context of anti-retroviral (ART) treatment. This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy. We also employed PET/CT-SCAN technology in these animals to help delineate the mechanism of virological control. Based on our in vitro and in vivo studies in NHPs we have identified a virus/host interaction that plays a pivotal role in HIV/SIV transmission and pathogenesis. One potential mechanism is signal transduction mediated by both natural ligands (e.g MAdCAM) and gp120 through alpha4beta7. Of note, MAdCAM co-stimulation through integrin-alpha4beta7 promotes HIV replication.